Rectal flunisolide compositions for treating inflammatory intestinal disorders

ABSTRACT

Topical rectal therapeutic composition containing, as the active ingredient, flunisolide and/or one or more ester derivatives of same, in combination with suitable excipients and/or diluents, for the treatment of inflammatory intestinal disorders.

This is a 371 of PCT/EP93/03228 filed Nov. 18, 1993.

FIELD OF THE INVENTION

The present invention relates to topical rectal therapeutic compositionscontaining, the as active ingredient, flunisolide and/or esterderivatives of same in combination with suitable excipients and/ordiluents, for the treatment of inflammatory intestinal disorders.

STATE OF THE ART

Among all inflammatory intestinal diseases, ulcerative colitis iscertainly the best known. It essentially affects the large intestine, inparticular and most severely the rectum, but sometimes, eithermarginally or entirely, the colon too.

Other types of inflammatory intestinal diseases may affect the rectumand result in a mild ulcerative colitis or in a slightly different, butpathologically similar syndrome, such as proctitis and sigmoiditis.

Another inflammatory intestinal disease is the so-called Crohn'sdisease, which affects the large intestine only marginally.

A known treatment of the above pathologies consists in the systemic andtopical administration of corticosteroids, such as hydrocortisone,betamethasone, and prednisolone.

However, the systemic administration of the aforesaid drugs producesserious side effects, mainly related to the interference with thehypothalamus-hypophysis-adrenal gland axis.

Also the topical administration of said corticosteroids causesinterference with the hypothalamus-hypophysis-adrenal gland axis, sincesaid drugs are inevitably absorbed by the systemic route. The sideeffects more frequently arising from the topical treatment of ulcerativecolitis with the aforesaid traditional corticosteroids are: transient orprolonged depression of adrenal gland functionality, weight increase,acne, and facies lunaris. It is to be noted that a characteristic ofulcerative colitis is an inflammed intestinal mucosa, which facilitatesthe systemic absorption of the drugs which are usually administered overan extended period of time. Therefore, the need of developing acorticosteroid exerting a high therapeutic activity in the treatment ofinflammatory intestinal diseases and involving a reduced systemicabsorption was deeply felt.

Takai et al. (J. Pharmacobiodyn. vol. 5, no. 3, 1982, pages 200-207,database Medline abstract) teach that flunisolide is highly active intopical use, while systemically it is relatively weak; thesecharacteristics could be attributable to its rapid metabolicinactivation in the liver. Nevertheless it gives no indication of theabsorption levels of fluticasone and its noxious effects, and there isno suggestion that it would be of use in treating inflammatoryintestinal disorders.

Flunisolide is a corticosteroid having formula ##STR1## and is used forthe treatment of asthma chiefly as nasal and bronchial topicalpreparations, of glaucoma as ophthalmic topical preparations, ofallergic or inflammatory conditions of the skin as creams and ointments.

This molecule is characterized by not high absorption levels and by ametabolic process (hepatic first pass) which rapidly transforms sameinto the metabolite 6-β-hydroxyderivative, whose glucocorticoid activityis approx. 350 times lower than that of flunisolide.

In other words, the amount of flunisolide inevitably absorbed by thesystemic way after topical application can never reach plasma levelsinterfering with the hypothalamus-hypophysis-adrenal gland axis.

THE PRESENT INVENTION

It has surprisingly been found that flunisolide and its estersadministered by the topical rectal way are very active in the treatmentof the aforesaid intestinal disorders and--unlike the steroids known sofar--do not cause the adverse effects related to the interference withthe hypothalamus-hypophysis-adrenal gland axis.

In fact, clinical trials carried out by the Applicant evidenced that animprovement of the basal symptomatology was obtained as early as after a15-day topical rectal treatment at doses of 2 mg/die and that a 3-mg/dieadministration for 30 days did not cause any appreciable clinicalmodification to cortisol plasmatic concentrations, an indicator of theinterference, if any, with the hypothalamus-hypophysis-adrenal glandaxis.

Object of the present invention is, therefore, a topical rectaltherapeutic composition containing, as active ingredient, flunisolideand/or one or more ester derivatives of same, in combination withsuitable excipients and/or diluents, for the treatment of inflammatoryintestinal disorders.

DETAILED DESCRIPTION OF THE INVENTION

The flunisolide used for the compositions of this invention is eitheranhydrous or in the corresponding hemihydrated form.

The expression "flunisolide ester derivatives" is used herein to meanthe derivatives in which one or both hydroxylic functions in positions11 and 21 of the aforesaid active ingredient have been esterified withC₂ -C₂₀ alkyl-, aryl- or arylalkyl- mono and/or polycarboxylic acids,with alkyl- or aryl mono and/or polysulphonic acids, aryl acidscontaining one or more carboxylic functions and one or more sulphonicfunctions and, in case of carboxylic and/or sulphonic polyfunctionalacids, the remaining acid functions are either partially or completelysalified with pharmaceutically acceptable cations, preferably sodium,potassium, magnesium, calcium.

Particularly preferred flunisolide esters are those formed with aceticacid, propionic acid, hexanoic acid, meta-sulfobenzoic acid and relativesodium meta-sulfobenzoate.

The compositions of the present invention are preferably in the form ofenemas, suppositories, and foams.

The suppositories of this invention contain from 0.5 to 10 mg each,preferably from 1 to 5 mg each of flunisolide and/or its esterderivatives.

In addition to the active ingredient, the suppositories of the presentinvention contain excipients preferably consisting of semisyntheticsolid glycerides of vegetable saturated fatty acids.

The rectal enemas of this invention are generally liquid compositions,solutions, emulsions or aqueous suspensions having an active ingredientcontent from 0-5 to 10 mg each, more preferably from 1 to 5 mg each, andgenerally containing preservatives, preferably selected among Parabens,chelating agents, such as for example ethylenediaminetetraacetic acid orthe relative sodium salt. Should said enemas be emulsions orsuspensions, they would also contain thickeners, such ascarboxymethylcellulose, and should they be solutions they would containthickeners-solubilizers, such as propylene glycol.

Said enemas may also contain compounds acting as pH regulators,preferably mineral or organic acids and/or pharmaceutically acceptablesalts.

The rectal foams have an active ingredient content preferably from 0.5to 10 mg/dose more preferably from 1 to 5 mg unitary dose.

Preferably, the rectal foams of this invention also contain:

traditional solubilizers, such as purified water and propylene glycol(the latter also acts as a thickener and is used for enemas) andsolubilizers also protecting the skin, essentially consisting of partialglycerides of polyoxyethylenic saturated fatty acids;

emulsifiers, such as polysorbate 20 and mixtures of cetostearylicalcohol with sorbitan esterified with polyoxyethylenic fatty acids;

chelating agents, such as ethylenediaminetetraacetic acid, also in theform of sodium salt;

preservatives, such as Parabens--also used for enemas;

acidifying buffers, such as phosphoric acid and monobasic sodium orpotassium phosphate;

propellants, such as hydrocarbons, e.g. isobutane, or fluorocarbons,e.g. dichlorodifluoromethane and dichlorotetrafluoroethane, orhydrochlorofluorocarbons or hydrofluorocarbons.

As concerns the pharmaceutical formulation, rectal foams--compared withenemas--have a lower water content and contain propellants, which areindispensable for dispensing the dose of drug to be administered.

It is just the presence of propellants that allows the dose dispensed ateach release of the pressure valve--in case of multidose bottles--or onpressure release valve--in case of single-dose bottles--to spread outand reach the inmost regions of the intestine, e.g. the colon leftsplenic flexure.

The propelling properties can vary depending on the type and quantity ofpropellant used and, consequently, the foam can reach more or lessdistant regions of the intestine.

The following examples of therapeutic compositions for topical rectaluse that are the object of this invention are conveyed by way ofindication, not of limitation.

A) Rectal foam

1) One 14-dose pressure bottle (2 mg anhydrous flunisolide/dose) and onesingle-dose (2 mg anhydrous flunisolide) pressure bottle contain:

    ______________________________________                                                         Multidose    Single-dose                                     ______________________________________                                        Anhydrous flunisolide                                                                            28     mg      2    mg                                     Cetostearylic alcohol +                                                                          830    mg      59.3 mg                                     sorbitan polyoxyethylenic                                                     esters                                                                        Polysorbate 20     553    mg      39.5 mg                                     Propylene glycol   11.38  g       956  mg                                     Glycerides of polyoxyethylenic                                                                   6.85           489  mg                                     saturated fatty acids                                                         Purified water     10.17  g       726  mg                                     Methyl p-hydroxybenzoate                                                                         39.5   mg      2.8  mg                                     Propyl p-hydroxybenzoate                                                                         7.9    mg      0.56 mg                                     Ethylenediaminetetraacetic acid                                                                  15.8   mg      1.13 mg                                     disodium salt                                                                 Monobasic sodium phosphate                                                                       313    mg      22.4 mg                                     Phosphoric acid q.s. to pH 5                                                  Dichlorodifluoromethane                                                                          2.53   g       616  mg                                     Dichlorotetrafluoroethane                                                                        3.79   g       922  mg                                     ______________________________________                                    

2) One 14-dose pressure bottle (2 mg hemihydrated flunisolide/dose) andone single-dose (2 mg hemihydrated flunisolide) pressure bottle contain:

    ______________________________________                                                         Multidose    Single-dose                                     ______________________________________                                        Hemihydrated flunisolide                                                                         28.58  mg      2.04 mg                                     Cetostearylic alcohol +                                                                          830    mg      59.3 mg                                     sorbitan polyoxyethylenic                                                     esters                                                                        Polysorbate 20     553    mg      39.5 mg                                     Propylene glycol   13.38  g       956  mg                                     Glycerides of polyoxyethylenic                                                                   6.85   g       489  mg                                     saturated fatty acids                                                         Purified water     10.17  g       726  mg                                     Methyl p-hydroxybenzoate                                                                         39.5   mg      2.8  mg                                     Propyl p-hydroxybenzoate                                                                         7.9    mg      0.56 mg                                     Ethylenediaminetetraacetic acid                                                                  15.8   mg      1.13 mg                                     disodium salt                                                                 Monobasic sodium phosphate                                                                       313    mg      22.4 mg                                     Phosphoric acid q.s. to pH 5                                                  Dichlorodifluoromethane                                                                          2.53   g       616  mg                                     Dichlorotetrafluoroethane                                                                        3.79   g       922  mg                                     ______________________________________                                    

3) One 14-dose pressure bottle (2 mg anhydrous flunisolide/dose) and onesingle-dose (2 mg anhydrous flunisolide) pressure bottle contain:

    ______________________________________                                                         Multidose    Single-dose                                     ______________________________________                                        Anhydrous flunisolide                                                                            28     mg      2    mg                                     Cetostearylic alcohol +                                                                          830    mg      59.3 mg                                     sorbitan polyoxyethylenic                                                     esters                                                                        Polysorbate 20     553    mg      39.5 mg                                     Propylene glycol   13.38  g       956  mg                                     Glycerides of polyoxyethylenic                                                                   6.85   g       489  mg                                     saturated fatty acids                                                         Purified water     10.17  g       726  mg                                     Methyl p-hydroxybenzoate                                                                         39.5   mg      2.8  mg                                     Propyl p-hydroxybenzoate                                                                         7.9    mg      0.56 mg                                     Ethylenediaminetetraacetic acid                                                                  15.8   mg      1.13 mg                                     disodium salt                                                                 Monobasic sodium phosphate                                                                       313    mg      22.4 mg                                     Phosphoric acid q.s. to pH 5                                                  Isobutane          3.16   g       769  mg                                     ______________________________________                                    

4) One 14-dose pressure bottle (2 mg hemihydrated flunisolide/dose) andone single-dose (2 mg hemihydrated flunisolide) pressure bottle contain:

    ______________________________________                                                         Multidose    Single-dose                                     ______________________________________                                        Hemihydrated flunisolide                                                                         28.58  mg      2.04 mg                                     Cetostearylic alcohol +                                                                          830    mg      59.3 mg                                     sorbitan polyoxyethylenic                                                     esters                                                                        Polysorbate 20     553    mg      39.5 mg                                     Propylene glycol   13.38  g       956  mg                                     Glycerides of polyoxyethylenic                                                                   6.85   g       489  mg                                     saturated fatty acids                                                         Purified water     10.17  g       726  mg                                     Methyl p-hydroxybenzoate                                                                         39.5   mg      2.8  mg                                     Propyl p-hydroxybenzoate                                                                         7.9    mg      0.56 mg                                     Ethylenediaminetetraacetic acid                                                                  15.8   mg      1.13 mg                                     disodium salt                                                                 Monobasic sodium phosphate                                                                       313    mg      22.4 mg                                     Phosphoric acid q.s. to pH 5                                                  Isobutane          3.16   g       769  mg                                     ______________________________________                                    

B) Suppositories

5) One suppository (2 mg anhydrous flunisolide) contains:

    ______________________________________                                        Anhydrous flunisolide                                                                            2 mg                                                       Glyceric esters of                                                                             1498 mg                                                      saturated fatty acids                                                         ______________________________________                                    

6) One suppository (2 mg hemihydrated flunisolide) contains:

    ______________________________________                                        Hemihydrated flunisolide                                                                         2.04 mg                                                    Glyceric esters of                                                                              1498 mg                                                     saturated fatty acids                                                         ______________________________________                                    

C) Enema

7) One 60 ml single-dose bottle (2 mg anhydrous flunisolide) contains:

    ______________________________________                                        Anhydrous flunisolide   2 mg                                                  propylene glycol       24 g                                                   Ethylenediaminetetraacetic acid                                                                      15 mg                                                  sodium salt                                                                   Hydrochloric acid      q.s. to pH 5                                           Purified water         q.s. to 60 ml                                          ______________________________________                                    

8) One 60 ml single-dose bottle (2 mg hemihydrated flunisolide)contains:

    ______________________________________                                        Hemihydrated flunisolide                                                                             2.04 mg                                                Propylene glycol         24 g                                                 Ethylenediaminetetraacetic acid                                                                        15 mg                                                sodium salt                                                                   Hydrochloric acid      q.s. to pH 5                                           Purified water         q.s. to 60 ml                                          ______________________________________                                    

The excipients of the above compositions are reported below.

Rectal foam

    ______________________________________                                        EXCIPIENT            FUNCTION                                                 ______________________________________                                        Cetostearyl alcohol containing                                                                     emulsifier                                               sorbitan esterified with                                                      polyoxyethylenic fatty acids                                                  Polysorbate 20       emulsifier                                               Partial glycerides of polyoxyethylenic                                                             solubilizer-skin protector                               saturated fatty acids                                                         Propylene glycol     solubilizer-thickener                                    Methyl p-hydroxybenzoate sodium salt                                                               preservative                                             Propyl p-hydroxybenzoate sodium salt                                                               preservative                                             Ethylenediaminetetraacetic acid                                                                    chelating agent                                          disodium salt                                                                 Purified water       solubilizing vehicle                                     Monobasic sodium phosphate and                                                                     pH regulating buffer                                     phosphoric acid                                                               Dichlorodifluoromethane                                                                            propellant                                               Dichlorotetrafluoroethane                                                                          propellant                                               Isobutane            propellant                                               ______________________________________                                    

Suppository

    ______________________________________                                        EXCIPIENT            FUNCTION                                                 ______________________________________                                        Semisynthetic solid glycerides                                                                     mass for supporitory                                                          (solid vehicle)                                          ______________________________________                                    

Enema

    ______________________________________                                        EXCIPIENT            FUNCTION                                                 ______________________________________                                        Propylene glycol     solubilizer-thickener                                    Ethylenediaminetetraacetic acid                                                                    chelating agent                                          sodium salt                                                                   Hydrochloric acid    acidifier                                                Purified water       solubilizing vehicle                                     ______________________________________                                    

CLINICAL TRIALS

FLUNISOLIDE ENEMA (2 and 3 mg)

Preliminary clinical trials were conducted with Flunisolide in the formof enema using No. 18 patients of both sexes suffering from ulcerativecolitis, limited to the splenic flexure. Patients were divided into twogroups and treated with 2 mg/die and 3 mg/die, respectively, for 30days.

The obtained results clearly indicate that the drug has an excellenttherapeutic efficacy and above all is well tolerated, especially inrelation to the inferference with the hypothalamus-hypophysis-adrenalgland axis.

In particular treatments with Flunisolide at a dose of 2 mg/die and 3mg/die for 15 and 30 days always produced statistically significantimprovements (Mann-Whitney's "U" test) of the basal sympotomatology asfar as the clinical and the sigmoidoscopic parameters are concerned (cf.Table 1 attached hereto).

As concerns drug toleration to the treatment and in particular theinterference with the hypothalamus-hypophysis-adrenal gland axis, thetreatment with flunisolide at the higher dose (3 mg/die) for 30 daysnever determined cortisolemia values below normality.

                  TABLE 1                                                         ______________________________________                                        Average values ± standard error of the mean of scores detected             basally (T.sub.0) and after 15 (T.sub.15) and 30 (T.sub.30) days of           treatment                                                                     with flunisolide at the dose of 2 and 3 mg/die. Results of the                statistical evaluation made by Mann-Whitney's "U" test compared               with the respective basal values.                                             (score 1 = normal; score 2 = mild; score 3 = moderate)                        PARAMETERS    T.sub.0    T.sub.15 T.sub.30                                    ______________________________________                                        Flunisolide 2 mg/die (No. 10)                                                 CLINICAL      2.7 ± 0.2                                                                             1.9 ± 0.2                                                                           1.5 ± 0.2                                              --         *        **                                          SIGMOIDOSCOPIC                                                                              2.7 ± 0.2                                                                             2.2 ± 0.1                                                                           1.6 ± 0.2                                              --         *        **                                          Flunisolide 3 mg/die (No. 8)                                                  CLINICAL      2.9 ± 0.1                                                                             2.0 ± 0.2                                                                           1.6 ± 0.2                                              --         **       **                                          SIGMOIDOSCOPIC                                                                              3.0 ± --                                                                              2.4 ± 0.2                                                                           2.1 ± 0.2                                              --         **       **                                          ______________________________________                                         *P ≦ 0.05;                                                             **P ≦ 0.01                                                        

We claim:
 1. A method of locally treating inflammatory intestinaldiseases comprising administering to a patient in need of such treatmenta pharmaceutically effective amount of flunisolide or a flunisolideester, said pharmaceutically effective amount being administered by atopical rectal route.
 2. Therapeutic method for the treatment ofulcerative colitis, inflammatory intestinal diseases resulting in mildulcerative colitis or in a slightly different, but pathologicallysimilar syndrome or of Chron's disease, comprising the topical, rectalapplication of a pharmaceutical composition containing as activeingredient anhydrous or hemihydrated flunisolide and/or one or moreester derivatives of same, in combination with suitable excipientsand/or diluents, said pharmaceutical composition containing between 0.5and 1 mg of active ingredient per unitary posological dose. 3.Therapeutic method according to claim 2 wherein the unitary posologicaldose is between 1 and 5 mg.
 4. Therapeutic method according to claim 2wherein the pharmaceutical composition is in the suppository form. 5.The therapeutic method according to claim 4 wherein said suppositoryform contains excipients selected from the group consisting ofsemisynthetic glycerides of vegetable saturated fatty acids.
 6. Thetherapeutical method according to claim 2 wherein the pharmaceuticalcomposition is in the rectal enema form.
 7. The therapeutic methodaccording to claim 6 wherein said rectal enema form is a solution, whichcontains preservatives chelating agents, pH regulators andthickeners-solubilizers.
 8. The therapeutic method according to claim 6wherein said rectal enema form is an emulsion or an aqueous suspension,which contains preservatives chelating agents, andthickeners-emulsifiers.
 9. The therapeutic method according to claim 2wherein the pharmaceutical composition is in the rectal foam form. 10.The therapeutic method according to claim 9 wherein said rectal foamform further comprises emulsifiers, water, thickeners-solubilizers, andthickeners-solubilizers also exerting a skin protective action,preservatives, chelating agents, acidifying buffers, and propellents.11. The therapeutic method according to claim 2 wherein the flunisolideester derivatives are those having one or both hydroxylic functions inpositions 11 and 21 of the aforesaid active ingredient eserified with C₂-C₂₀ alkyl-, aryl- or arylalkyl- mono and/or polycarboxylic acids, withalkyl- or aryl mono and/or polysulphonic acids, aryl acids containingone or more carboxylic functions andone or more sulphonic functions and,in case of carboxylic and/or sulphonic polyfunctional acids, theremaining acid functions are either partially or completely salifiedwith pharmaceutically acceptable cations.
 12. The therapeutic methodaccording to claim 2 wherein the used flunisolide esters are the estersformed with acetic acid, propionic acid, hexanoic acid,meta-sulfobenzoic acid and relevant sodium meta-sulfobenzoate.